TY - JOUR T1 - Novel Mechanism of Chronic Exposure of Oleic Acid-Induced Insulin Release Impairment in Rat Pancreatic β-Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1203 LP - 1210 DO - 10.1124/jpet.106.105759 VL - 318 IS - 3 AU - Takanori Kudo AU - Jie Wu AU - Yoshiji Ogawa AU - Sechiko Suga AU - Noriyuki Hasegawa AU - Toshihiro Suda AU - Hiroki Mizukami AU - Soroku Yagihashi AU - Makoto Wakui Y1 - 2006/09/01 UR - http://jpet.aspetjournals.org/content/318/3/1203.abstract N2 - A sustained, high circulating level of free fatty acids (FFAs) is an important risk factor for the development of insulin resistance, islet β-cell dysfunction, and pathogenesis of type 2 diabetes. Here, we report a novel mechanism of chronic exposure of oleic acid (OA)-induced rat insulin release impairment. Following a 4-day exposure to 0.1 mM OA, there was no significant difference in basal insulin release when comparing OA-treated and untreated islets in the presence of 2.8 mM glucose, whereas 16.7 mM glucose-stimulated insulin release increased 2-fold in control, but not in OA-treated, islets. Perforated patch-clamp recordings showed that untreated β-cells exhibited a resting potential of -62.1 ± 0.9 mV and were electrically silent, whereas OA-treated β-cells showed more positive resting potentials and spontaneous action potential firing. Cell-attached single-channel recordings revealed spontaneous opening of ATP-sensitive potassium (KATP) channels in control, but not in OA-treated, β-cells. Inside-out excised patch recordings showed similar activity in both OA-treated and untreated β-cells in the absence of ATP on the inside of the cellular membrane, whereas in the presence of ATP, KATP channel activity was significantly reduced in OA-treated β-cells. Electron microscopy demonstrated that chronic exposure to OA resulted in the accumulation of triglycerides in β-cell cytoplasm and reduced both the number of insulin-containing granules and insulin content. Collectively, chronic exposure to OA closed KATP channels by increasing the sensitivity of KATP channels to ATP, which in turn led to the continuous excitation of β-cells, depletion of insulin storage, and impairment of glucose-stimulated insulin release. The American Society for Pharmacology and Experimental Therapeutics ER -